Transcript BioN08 Metabolism of lipids Summer 2015

Metabolism of lipids
Dr. Mamoun Ahram
Biochemistry for Nursing
Summer 2015
Sources of lipids
• They enter the pathways
– from the digestive tract as food is broken down,
– from adipose tissue, where excess lipids have been
stored
• fatty acids released from adipose tissue associate with
albumin and are transported to other tissues
– from the liver, where lipids are synthesized.
Digestion of triglycerides
Why do we fell full when we eat fatty
food?
• The presence of triacylglycerols in consumed food
slows down the rate at which the mixture of partially
digested foods leaves the stomach
Digestion of triglycerides
• Lipases are released
from pancreas.
• Bile is released from
gallbladder to emulsify
lipids
– Cholic acid is the major
bile
Cholic acid (just like soap)
Bile acids are derived from
cholesterol
Pancreatic lipase
Interstitial villi
Lacteal (lymphatic vessel)
Lipid absorption
• Small fatty acids and glycerol
are water-soluble and are
absorbed directly through the
surface of the villi.
• The water-insoluble
acylglycerols and larger fatty
acids are released from the
micelles at the intestinal
lining and absorbed.
Lipoproteins
Because lipids are less dense than proteins, the density of lipoproteins
depends on their ratio of lipids to proteins.
Therefore, lipoproteins can be divided into five major types
distinguishable by their composition and densities.
Transport of lipids
to
peripheral
tissues
back to the
liver, where it
is converted
to bile acids.
Chylomicrons
• Chylomicrons are too large to enter the bloodstream
through capillary walls.
• Instead, they are absorbed into the lymphatic system
through lacteals within the villi and are carried to the
thoracic duct where the lymphatic system empties
into the bloodstream.
• These are the lowest-density lipoproteins because
they carry the highest ratio of lipids to proteins.
Good versus bad cholesterol
• LDL (the so-called bad cholesterol) delivers more cholesterol
than is needed to peripheral tissues
– if not enough HDL (the so-called good cholesterol) is
present to remove it, the excess cholesterol is deposited in
cells and arteries.
• LDL also can trigger inflammation and the buildup of plaque in
artery walls.
Lipoprotein lipase (LPL)
• TAGs in chylomicrons are
hydrolyzed in the
bloodstream by lipoprotein
lipases that are anchored in
capillary walls.
• The resulting fatty acids
have two possible fates:
(1) When energy is in good
supply, they are converted
back to TAGs for storage in
adipose tissue.
(2) (2) When cells need
energy, the fatty acid
carbon atoms are oxidized
into acetyl-SCoA.
Fate of fatty acids
Hydrolysis/
mobilization
For storage
In adipose
tissues
Lipogenesis
Protein
metabolism
Steroids
Ketogenesis
Lipases of adipocytes
Inhibited by insulin
Activated by glucagon
• When energy is needed, lipases within fat cells are
activated by hormones (insulin and glucagon).
• The stored TAGs are hydrolyzed to fatty acids, and
the free fatty acids and glycerol are released into
• the bloodstream.
• The fatty acids travel in association with albumins
to cells where they are converted to acetyl-CoA for
energy generation.
Glycerol
The glycerol produced from
TAG hydrolysis is carried in
the bloodstream to the
liver or kidneys, where it is
converted to glyceraldehyde 3phosphate and
dihydroxyacetone phosphate
(DHAP)
Links lipid and
carbohydrate
metabolism
Adipocytes do not have the
kinase needed to convert
glycerol to glycerol 3phosphate, they cannot
synthesize triacylglycerols
Leptin and grehlin
• Leptin, a peptide hormone, is synthesized in
adipocytes and acts on the brain to stop eating it
suppresses appetite.
• Grehlin, another peptide hormone, stimulates
intense sensations of hunger.
Synthesis of triacylglycerols
After a meal, blood glucose levels increase rapidly, insulin levels rise, and
glucagon levels drop. Glucose enters cells, and the rate of glycolysis
increases.
Under these conditions, insulin activates the synthesis of TAGs for
storage.
The basic
phospholipid
Oxidation of fatty acids
• The purpose is to produce coenzymes (NADH and
FADH2) that will enter the elelctron transport chain
and produce ATP.
• This is done in four stages:
– Activation
– Transport
– Beta-oxidation
Activation of fatty acid
• The fatty acid must be activated by conversion to
fatty acyl-SCoA.
• This activation, which occurs in the cytosol.
• ATP is consumed.
Transport into mitochondrial matrix
• The fatty acyl-SCoA cannot cross the mitochondrial
membrane by diffusion and must be transported from the
cytosol into the mitochondrial matrix.
• Carnitine is the carrier by forming a fatty acyl-carnitine ester.
Beta-oxidation
• Step 1: Acyl-CoA dhydrogenase
and its coenzyme FAD remove
hydrogen atoms forming (C=C)
and forming FADH2.
• Step 2: The (C=C) is hydrated
into (OH-) group.
• Step 3: the (-OH) group is
oxidized into a carbonyl group
(C=O) and NAD+ is reduced.
• Step 4: the acetyl group is
detached to a coenzyme A and
the fatty acid is 2 carbons
shorter.
How much energy is produced from
beta-oxidation of a fatty acid?
• Know number of carbons of a fatty acid
– Divide by two. This gives you the number of acetyl CoA
produced from this fatty acid that will enter the citric acid
cycle
• Each acetyl CoA produces 1 ATP, 3 NADH, and 1 FADH2.
– 1 NADH = 2.5 ATP molecules; 1 FADH2 = 1.5 ATP molecules
• Each cycle of beta-oxidation produces 1 NADH and 1
FADH2. This equals 4 ATP molecules.
– Number of cycles = number of acetyl CoA – 1
• Subtract 2 ATP molecules needed to activate the
fatty acid
Exercises
• How many ATP molecules can lauric acid (a 12carbon fatty acid)? Lauric acid is equivalent to
glucose (similar molecule weight). Compare
production of ATP by lauric acid to that of glucose
(glucose can produce 30-35 ATP molecules).
• How much ATP does beta-oxidation of palmitic acid
produce?
Ketone bodies
• They are produced in
the liver when there is
excess lipid catabolism
• They are hydrphilic
– They can travel though
the bloodstream without
the need of a carrier
Ketogenesis (know the steps)
• ketone bodies do not need protein carriers to travel in the
bloodstream. Once formed, they become available to all tissues.
•Location: mitochondria
•Acetone is formed in the
bloodstream by the nonenzymatic decomposition
of acetoacetate and is
excreted by exhalation.
Reversal of last step
of -oxidation
Use of ketone bodies (important)
• The skeletal muscles of a well fed and healthy person derive a
small portion of their daily energy needs from acetoacetate.
• Heart muscles prefer ketone bodies over glucose when fatty
acids are in short supply.
• When energy production from glucose is inadequate due to
starvation, the production of ketone bodies accelerates.
• During the early stages of starvation, heart and muscle tissues
burn larger quantities of acetoacetate, to preserve glucose for
use in the brain.
• In prolonged starvation, the brain gets 75% of its energy
needs by switching to ketone bodies.
Ketosis
• Overproduction of ketone bodies (diabetes)
• Ketosis results in:
– Ketonuria (ketone bodies in urea)  dehydration
– Ketonemia (ketone bodies in blood)
– Ketoacidosis (drop in blood pH)  labored breathing
Ketoacidosis
• Because two of the ketone bodies are carboxylic
acids, continued ketosis (as in untreated diabetes)
leads ketoacidosis (acidosis resulting from increased
concentrations of ketone bodies in the blood).
• The blood buffers cannot control blood pH, which
drops.
• An individual experiences dehydration due to
increased urine flow, labored breathing because
acidic blood is a poor oxygen carrier, and depression.
• Ultimately, if untreated, the condition leads to coma
and death.
Start of lipogenesis
(biosynthesis of fatty acids)
• Excess of acetyl-CoA from
catabolism of carbohydrates
and proteins are diverted
into formation of fatty acids
that can then be stored.
• Location: cytosol
• Production of acetyl-CoA and
malonyl-CoA, which are
linked to acyl-carrier protein
(ACP) in the enzyme
• Note: need of ATP
Link to enzyme
via ACP
Link to enzyme
via ACP
Fatty acid synthase
• It is a multienzyme
complex that contains
all six of the enzymes
needed for lipogenesis,
with a protein called
acyl carrier protein
(ACP) anchored in the
center of the complex.
• Remember: pyruvate
dehydrogenase complex
Lipogenesis
• Condensation, reduction, dehydration, reduction
Note; use of NADPH
Repeat steps
In each step, malonylCoA is added to the
reaction
Lipogenesis
(Biosynthesis of fatty acids)
Site of reaction
Oxidation
Synthesis
Mitochondria
Cytosol
Enzymes
Different from each other
Carrier of intermediates
Coenzyme A
Acyl carrier proteins
Conenzymes
FAD, NAD
NADPH
Carbon removal and
addition
Two carbons removed at a
time
Two carbons added at a
time
Can proteins be used to produce energy?
• Yes, but when?
– When the body does not have lipids and
carbohydrates to produce energy